DESCRIPTION: (Applicant's Abstract) The neurobiological mechanisms underlying the subjective, reinforcing effects, and discriminative stimulus effects of psychomotor stimulants have been investigated extensively in nonhumans. In general, these studies have indicated that dopaminergic pathways play a crucial role in drug-taking behavior, particularly those pathways that are part of the reward circuitry. However, laboratory studies in humans, such as those involving the administration of specific dopamine agonists and antagonists, have not replicated animal findings and treatment approaches using dopamine antagonists have not been successful. There is increasing evidence that serotonin systems interact with dopaminergic pathways, modulate dopamine release, and can reduce self-administration of psychostimulants in animals. The main goal of the experiments described in this proposal is to increase our understanding of the interaction between serotonin and dopamine systems in mediating the subjective, discriminative stimulus, and reinforcing effects of psychostimulant drugs in humans. This proposal will use three primary approaches to study serotonin/dopamine interactions: first, a drug with mixed serotonin/dopamine properties, 3,4,-methylendioxymethamphetamine (MDMA), will be compared with drugs with more selective dopamine (e.g. d-amphetamine) vs. serotonin (e.g., d-fenfluramine) mechanisms of action; second, d-amphetamine and d-fenfluramine will be coadministered in such a way as to produce mixed serotonin/dopamine effects which will be compared to the effects of the compounds administered alone; third, serotonin-mediated effects will be blocked by fluoxetine or tryptophan depletion in order to isolate the effects of dopamine with the expectation that serotonin blockade will have differential effects on the subjective, reinforcing, behavioral, and neurochemical effects on d-amphetamine, d-fenfluramine, and MDMA. In addition, these studies will provide objective data on the neurochemical, neurohormonal, subjective and reinforcing effects of MDMA under standardized laboratory conditions. Most importantly for the primary goal of this K08 Award, these studies will provide the PI with the opportunity to receive specialized training in substance abuse research methodology, an essential step in the goal of becoming an independent, productive drug abuse researcher.